Biomedical foams

ABSTRACT

The invention relates, generally, to porous absorbent materials which are suitable for packing antrums or other cavities of the human or animal body. More particularly, it relates to hydrophilic biodegradable foams, which may be used e.g. in the form of a plug or tampon, for instance for controlling bleeding, wound closure, prevent tissue adhesion and/or support tissue regeneration. The invention provides an absorbent foam, suitable for packing antrums or other cavities of the human or animal body, comprising a biodegradable synthetic polymer, which polymer preferably comprises —C(O)—O— groups in the backbone of the polymer, for instance polyurethane and/or polyester units combined with polyethers.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a division of U.S. patent application Ser. No.11/178,259, filed Jul. 8, 2005, and entitled “Biomedical Foams” which isa continuation of PCT/NL04/00010, filed on Jan. 8, 2004, which claimspriority to European Patent Application No. 03075065.7, the entirety ofeach is hereby incorporated by reference.

FIELD OF THE INVENTION

The invention relates, generally, to biodegradable porous absorbentmaterials which are suitable for packing antrums or cavities of thehuman or animal body. More particularly, it relates to biodegradableabsorbent foams, which may be used e.g. in the form of a plug, tampon orsheet, for instance for controlling bleeding (a haemostatic sponge),wound closure and/or support tissue regeneration.

DESCRIPTION OF THE PRIOR ART

Nasal packing is the application of packs to the nasal cavities. Themost common purpose of nasal packing is to control bleeding followingsurgery to the septum or nasal reconstruction, to prevent synechiae(adhesion) or restenosis and to treat epistaxis (nose bleeding). Packingis also used to provide support to the septum after surgery.

In cases of septoplasty and rhinoplasty surgery, conventionalnon-biodegradable packings are frequently removed within 24-48 hoursfollowing surgery. In the case of epistaxis, packing is left in forextended periods of time to promote healing and to prevent the patientfrom touching and accidentally interfering with the recovery of thewound. The packing may be left in the nose for as long as 7-10 days. Ifthe wound is high up in the nasal cavity, packings treated withpetrolatum and/or antibiotics are sometimes used. In the art, biodurablewound dressings are used for nasal packing. These biodurable packs haveto be removed after several days as described above. Removing the packwhen the wound is still fresh may damage the nasal cavity again and isassociated with patient discomfort. In some cases this is evenassociated with a vaso-vagal reaction followed by fainting of thepatient.

Numerous materials have been proposed in the prior art for use as dentaland biomedical foams for absorbing or removing body fluids. Conventionalpacks consisting of gauze or cotton have several disadvantages: thefluid absorption capacity of the material is relatively low, thestructure is relatively fragile and individual threads or fibres maybreak off, erroneous failure to remove the material from the body afterinternal surgery may lead to serious complications and the material isrelatively expensive.

Certain hydrophilic synthetic materials intended for biomedicalapplications have improved properties when compared to conventionalmaterials when it comes to absorption capacities and physico-mechanicalproperties. Examples of such material are the cross-linkedpolyurethane-based hydrogels as disclosed in e.g. U.S. Pat. No.3,903,232, U.S. Pat. No. 3,961,629, U.S. Pat. No. 4,550,126 and EP-A-0335 669. However, these materials are biodurable and not biodegradable.

This lack of biodegradability makes such materials less suitable for usein body cavities during surgery, since there is always a possibilitythat the foam is left accidentally in the body. Furthermore, removingnon-biodegradable foams after application in a natural body orifice maybe very uncomfortable for a patient and may open up the wound and/orlead to additional scarring of the tissue.

In order to prevent these undesired effects, biodegradable sponges orabsorbing foams comprising materials of a natural source such asgelatine, proteins (collagen), chitin, cellulose or polysaccharides havebeen suggested. However, all of these materials lack the requiredmechanical strength. For example, the haemostatic sponge of denaturatedgelatin of WO 90/13320 does not have sufficient mechanical strength tostop a severe nose-bleeding, because the compression strength of thematerial in the wet condition is too low and the sponge liquefies toofast after being applied in the nasal cavity. Furthermore, properties ofnatural polymers are difficult to control; they may have batch to batchvariations, and they are generally more expensive than syntheticmaterials. Also, biodegradable material of natural sources, especiallyof animal origin, is not preferred, because of the biological hazardsassociated with its use.

Synthetic surgical dressings that are absorbable by the body have beendisclosed in a few patent applications. U.S. Pat. No. 3,902,497 and U.S.Pat. No. 3,875,937 disclose surgical dressings of bio-absorbablepolymers of polyglycolic acid (PGA). Such materials are, although usefulin other applications, not useful in applications where sufficientcounter pressure from the foam is required, such as in nose-bleeding,because the material is quite hard and brittle and is not resilient.Therefore, the physical properties of the PGA-based foams are not suitedfor application in many medical situations. Moreover, the PGA materialis not sufficiently hydrophilic to absorb the blood during severebleeding. In order to control severe bleeding, foams preferably exhibithigh absorption capacities due to the hydrophilic nature of thematerial.

The need for synthetic absorbable sponges or absorbent foams that can beleft in the wound is now well recognized. Requirements of such foams area) a high (fluid) absorption capacity, particularly for blood, b) rapidabsorption of fluid, c) strength to be readily handled in surgicalprocedures, d) conformable so as to fit into any topography or space, e)maintenance of mechanical properties, such as resilience, for a specificperiod of time during or after surgery or after application of the foam,and f) soft so as to avoid injury to sensitive tissues. In someinstances, the softness of the foam may be increased by wetting of thefoam. Therefore, the absorbing foam should also have enough mechanicalstrength and elasticity in the wet condition.

There is a need for bio-compatible, biodegradable synthetic foams thatcan be applied as medical sponges or as wound dressings with improvedphysical and mechanical properties. It is a particular objective of thepresent invention to overcome the drawbacks and the problems associatedwith the sponges and absorbent foams of the prior art and to provide afoam material that is biodegradable, that is able to absorb liquids orbody fluids and that has improved mechanical properties, such as a highelasticity, even when wet.

SUMMARY OF THE INVENTION

It has now surprisingly been found that a biodegradable absorbent foamcomprising a phase-separated polymer consisting of an amorphous segmentand a crystalline segment and wherein at least said amorphous segmentcomprises a hydrophilic segment provides improved physical andmechanical properties for packing antrums or other cavities of the humanor animal body and does not suffer from the disadvantages of the spongesof the prior art.

According to the present invention, the amorphous segment must comprisea hydrophilic segment. This amorphous segment, also called the amorphousphase in the art, is amorphous when packed in an antrum or other cavityof the human or animal body, i.a. when wet, in the wet state, despitethe fact that it may comprise a crystalline polyether. This means that,in the dry state, said crystalline polyether may provide the amorphousphase of the polymer with partially crystalline properties. Theperformance of the foam in the packed state determines thecharacteristics of the foam: in the packed state, the foam of theinvention is comprised of an amorphous hydrophilic soft segment or phaseand a crystalline hard segment or phase.

The phase-separated character of the polymer from which the foam of theinvention is comprised, provides the material with very suitablecharacteristics. The presence of hydrophilic segment or group in theamorphous phase of the polymer from which the foam of the invention iscomprised further provides said foam with required characteristics suchas the capacity to absorb aqueous liquids and being readilybiodegradable.

Hydrophilic groups may also be present in the hard segment of thepolymer, but the presence of hydrophilic groups in the hard segmentshould not result in immediate disintegration of the foam when placed incontact with fluids. Essentially, the crystalline hard segment or phasemust provide the foam with rigidity, keep the foam intact and preventswelling of the foam when placed in contact with fluids. Also, a foam ofthe invention may comprise more than one amorphous segment or phase.

In a first aspect, therefore, the present invention provides abiodegradable absorbent foam, suitable for packing antrums or othercavities of the human or animal body, comprising a phase-separatedpolymer consisting of an amorphous segment and a crystalline segment andwherein said amorphous segment comprises a hydrophilic segment.

In one embodiment of said aspect, a biodegradable absorbent foam isprovided which foam comprises a polymer of the formula:

—[R-Q¹[—R′—Z¹—[R″—Z²—R′—Z³]_(p)—R″—Z¹]_(q)—R′-Q²]-_(n)  (I),

wherein R is selected from one or more aliphatic polyesters,polyetheresters, polyethers, polyanhydrides and/or polycarbonates, andat least one R comprises a hydrophilic segment, R′ and R″ areindependently C₂-C₈ alkylene, optionally substituted with C₁-C₁₀ alkylor C₁-C₁₀ alkyl groups substituted with protected S, N, P or O moietiesand/or comprising S, N, P or O (e.g. ether, ester, carbonate and/oranhydride groups) in the alkylene chain, Z¹-Z⁴ are independently amide,urea or urethane, Q¹ and Q² are independently urea, urethane, amide,carbonate, ester or anhydride, n is an integer from 5-500, p and q areindependent 0 or 1, provided that when q is 0, R is a mixture of atleast one crystalline polyester, polyetherester or polyanhydride segmentand at least one amorphous aliphatic polyester, polyether, polyanhydrideand/or polycarbonate segment. The O containing moieties in the alkylenechain, if present, are preferably hydrophilic groups, in particularether groups, since such hydrophilic groups can provide a reduceddegradation time to the polymer, which may be desirable for thepolymer's use in implants.

The simplest form of the polymer from which a foam of the invention maybe comprised is of the formula: —R-Q¹-R′-Q²-, i.e. when q=0.

According to the present invention, the amorphous segment is comprisedin the —R— part of the polymer according to formula (I). In case q=1,the Q¹[—R′—Z¹-[R″—Z²—R′—Z³]_(p)—R″—Z⁴]_(q)—R′-Q² part of the polymeraccording to formula (I) represents the crystalline segment. In thisparticular case the amorphous and crystalline segments are alternating,thus providing the hard segment with a uniform block-length.

As described above, R may represent a mixture of two or more differenttypes of aliphatic polyesters, polyetheresters, polyethers,polyanhydrides and/or polycarbonates, which mixture comprises bothamorphous and crystalline types, so that both are comprised in a foam ofthe invention. In the case that a mixture of amorphous and crystallinetypes of R segments are provided in a polymer according to the formula(I), at least one hydrophilic segment is provided in at least oneamorphous R segment.

In a polymer according to the formula (I), Q¹ and Q² may be selectedfrom amide, urea, urethane ester, carbonate or anhydride groups, whereasZ¹ through Z⁴ should be chosen from amide, urea or urethane groups sothat at least 4 hydrogen bond forming groups are present in a row in thecrystalline segment. The group R in —Z²—R′—Z³— may be different orsimilar to R′ in -Q¹-R′—Z¹— or —Z⁴—R′-Q²-.

As stated, R comprises a hydrophilic segment and such a hydrophilicsegment can very suitably be an ether segment, such as a polyethersegment derivable from such polyether compounds as polyethyleneglycol,polypropyleneglycol or polybutyleneglycol. Also, a hydrophilic segmentcomprised in R may be derived from polypeptide, poly(vinyl alcohol),poly(vinylpyrrolidone) or poly(hydroxymethylmethacrylate). A hydrophilicsegment is preferably a polyether.

In an alternative embodiment, a biodegradable absorbent foam is providedby the present invention, which foam comprises a polymer of the formula:

—[R-Q¹-R′″-Q²-]_(n)  (II)

wherein R, Q¹, Q² and n are as described above, Q¹ and Q² areindependently, urea, urethane, amide, carbonate, ester or anhydride,preferably urea, urethane or amide, R′″ is chosen from R, R′ or R″ asdescribed above, provided that when R′″ is R′ or R″, R is a mixture ofat least one crystalline polyester, polyetherester or polyanhydride andat least one amorphous aliphatic polyester, polyether, polyanhydrideand/or polycarbonate. When R′″ is R, at least one crystalline polyester,polyetherester or polyanhydride and at least one amorphous aliphaticpolyester, polyether, polyanhydride and/or polycarbonate is provided insaid polymer. Again, a hydrophilic segment is then provided in saidamorphous segment of the phase-separated polymer and the amorphous andcrystalline segments are alternating.

In a further aspect, the present invention provides a phase-separatedbiodegradable polymer of the formula (I) as defined above.

In yet another aspect, the present invention provides a method forpreparing a phase-separated biodegradable polymer of the formula (I)according to the invention, comprising reacting:

one or more pre-polymers of the formula:

A-R-A′  (III),

with one or more diisocyanates of the formula:

O═C═N—R′—N═C═O  (IV)

and optionally one or more chain extenders of the formula:

B—R″—B′  (V)

wherein R, R′, and if are as defined in formula (I), and A, A′, B and B′are independently selected from hydroxyl, carboxyl or amine. Preferable,the chain extension reaction with (reaction products of) above compounds(III), (IV) and (V) are performed in a solvent, more preferably in1,4-dioxane or trioxane, even more preferably 1,4-dioxane. In an evenmore preferred embodiment, a reaction between compounds (III) and (IV)is performed in bulk after which a so called chain extension reaction isperformed with compound (V) in a solvent.

In an alternative of this embodiment, a reaction between compounds (IV)and (V) is performed in bulk after which a so called chain extensionreaction is performed with compound (III) in a solvent. By choosing thesequence of reacting the compounds of the formulas (III), (IV) and (V)with each other, i.e., first (III) and (IV) and then (V), or,alternatively, first (IV) and (V) and then (III), the organization andproperties of the resulting polymer can be adapted and controlled.

In order to provide for phase-separated polymers with even betterproperties the sequence of reacting the compounds of the formulas (III),(IV) and (V) with each other can be further adapted, for instance, byfirst reacting the compounds of the formulas (IV) and (V) to form anintermediate complex. Depending on the molar ratio's of the compounds(IV) and (V) used (i.e. one of the compounds should be present in excessover the other), either a diisocyanate according to the formula:

O═C═N—R′—Z¹—R″—Z²—R′—N═C═O  (VI)

is formed, with R′, R″, Z¹ and Z² as defined above, or a compound withend-groups of hydroxyl, carboxyl or amine, i.e. a compound of theformula:

B—R″—Z¹—R′—Z²—R′—B′  (VII),

wherein R′, R″, Z¹, Z², B and B′ are as defined above.The compound (VI), i.e. the intermediate diisocyanate complex, candirectly be used in a reaction with the compound of the formula (III),whereas the compound (VII), i.e. the intermediate compound withend-groups of hydroxyl, carboxyl or amine, is again reacted with excessdiisocyanate of the formula (IV) to yield a diisocyanate of the formula:

O═C═N—R′—Z¹—R″—Z²—R′—Z³—R″—Z⁴—R′—N═C═O  (VIII),

wherein R′, R″ and Z¹-Z⁴ are as defined above, which compound (VIII) isthen used in a reaction with the compound (III) to yield a polymer ofthe invention.

The result of this latter method is a phase-separated biodegradablepolymer of the formula (I) wherein the elements R′ and R″ are comprisedin the alternating form of a R′—R″—R′—R″—R′ segment, and wherein theelements R′ and if are linked by various types of chemical bonds Z.

This polymeric structure can also be prepared by an alternative methodwherein a compound of the formula (IV) is reacted with excess compoundof the formula (V) to yield an intermediate compound of the formula(VII) followed by reacting this intermediate compound with anotherintermediate compound of the formula:

O═C═N—R′—Z¹—R—Z²—R′—N═C═O  (IX),

generated by reacting the compound of the formula (III) with an excessof the compound of the formula (IV). The reaction between a compound ofthe formula (VII) with a compound of the formula (IX) will result in theformation of a polymeric compound with the segment sequence—R′—R—R′—R″—R′—R″—.

A polymer of formula (I) and with q=0 (or formula (II) with R′″═R′), canbe obtained by a chain-extension reaction of at least two compounds offormula (III) with a compound of formula (IV) provided that R is amixture of at least one crystalline polyester, polyetherester orpolyanhydride segment and at least one amorphous aliphatic polyester,polyether, polyanhydride and/or polycarbonate segment containing ahydrophilic group.

The polymer of the present invention may be produced in bulk, or, morepreferably, it may be produced in a solvent. A very suitable suchsolvent is 1,4-dioxane or trioxane. The advantage of producing a polymerof the present invention in a solvent is that a very advantageousstarting material is thus provided for the preparation of a foam of theinvention. This starting material is already present in the form of asolution, and no time-consuming dissolution of polymers in solventsneeds to be accomplished. Most preferred is the use of the solvent1,4-dioxane.

In another aspect, the present invention provides a method for preparinga foam of the invention, comprising providing a solution of aphase-separated polymer, which polymer comprises an amorphous segmentand a crystalline segment and wherein at least the amorphous segmentcomprises a hydrophilic segment, in 1,4-dioxane or trioxane, freezingthe solution, and subliming the solvent by freeze-drying. Freeze dryingmay be performed by standard methods known in the art.

In an alternative embodiment, a foam of the invention may be prepared bya method comprising providing a phase-separated biodegradable polymerand forming said polymer into a foam of the invention, for example, byusing a blowing agent in a extrusion method as known in the art. Such anextrusion method may for instance comprise the melting of said polymerand the extrusion of the melt thus formed into a foam by the aid of agas, preferably a gas such as carbon dioxide.

In yet another alternative embodiment, a foam of the invention may forinstance be prepared by a method comprising preparing a phase-separatedbiodegradable polymer of the formula (I) by reacting a diisocyanatemolecule of the formula (IV), or one of the intermediate diisocyanatecompounds (VI), (VIII) or (IX) as described above, with a dicarboxylicacid or hydroxycarboxylic acid of the formula (III) and/or (V),optionally in combination with a di-hydroxyl pre-polymer of the formula(III) and optionally in the presence of water, and allowing in situgeneration of carbon dioxide during the completion of the polymerizationreaction. The ratio of isocyanate groups to carboxyl and hydroxy groups(including water) should preferably be close to 1.

In a preferred embodiment, however, a method for preparing abiodegradable absorbent foam, suitable for packing antrums or othercavities of the human or animal body, comprises preparing a polymeraccording to the invention in 1,4-dioxane or trioxane, diluting thepolymer solution during polymerization with the solvent, freezing thereaction mixture, and subliming the solvent, as stated above.

In yet another embodiment, a foam of the invention may be prepared by amethod comprising preparing a phase-separated biodegradable polymer ofthe formula (II) by reacting at least two different compounds accordingto formula (III) with each other. In this case R comprises at least onehydrophilic segment and at least one compound according to formula (III)provides a crystalline segment, and at least a second compound accordingto formula (III) provides an amorphous segment, said at least onehydrophilic segment being provided in said amorphous segment (R′″ is Rin formula (II)). Alternatively, compounds of formula (III) can bereacted with a compound of the formula (V) or (VII) and in combinationwith a chain extension reaction in the presence of an activator, such asN-hydroxysuccinimide or derivatives, carbonyldiimidazole, aldehydes,maleimides or dicycloxexyl carbodiimide (DCC). Such reactions are wellknown in the art.

In a further aspect, the present invention provides a biodegradablesynthetic absorbent foam, suitable for packing antrums or other cavitiesof the human or animal body, obtainable by a method of the presentinvention.

In a final aspect, the present invention relates to the use of a foamaccording to the invention as a haemostatic sponge, as a wound dressingmaterial, as a packing for antrums or other cavities of the human oranimal body, including dental packs, or as a drug delivery vehicle, aswell as to the use of a phase-separated biodegradable polymer of theinvention for the manufacture of a foam of the invention.

DESCRIPTION OF THE FIGURES

FIG. 1 shows schematically suitable shape and dimensions of apolyethyleneglycol-containing polyurethane foam according to theinvention for intended use as a nasal dressing.

FIG. 2 shows the thermal behaviour of foams ofpolyethyleneglycol-containing polyurethanes of the invention withdifferent pre-polymer composition, sterile and non-sterile, as describedin the results and discussion to the examples.

FIG. 3 shows the water absorption capacity of foam prepared from a (3/1)((50/50)glycolide-ε-caprolactone)/PEG1000 (w/w) based polyurethane, asdescribed in the results and discussion to the examples.

FIG. 4 shows the intrinsic viscosity of three PU foams vs. theirdegradation time at 37° C., as described in the results and discussionto the examples.

FIG. 5 shows the time until fragmentation vs the intrinsic viscosity of1.8% foams based on (1/1) ((50/50)lactide-ε-caprolactone)/PEG1000 (w/w)in a buffer solution at 37° C. upon action of a weight of 50 grams asdescribed in the results and discussion to the examples.

FIG. 6 shows the experienced patient discomfort during removal of anasal dressing (Nasopore) of the experimental group (with a dressingaccording to a foam of the present invention) vs. the control group (abiodurable dressing).

FIG. 7 shows the occurrence of nose bleedings during removal of a nasaldressing (Nasopore) of the experimental group (with a dressing accordingto a foam of the present invention) vs. the control group (a biodurabledressing).

DETAILED DESCRIPTION OF THE INVENTION

The term “sponge” is understood to mean a porous structure characterizedin that the structure is reticulate and has an inner surfaceconsiderably larger than its outer surface, that it contains hollowspaces (pores) within the reticulate structure and that it can absorbmany times its own weight in liquids in a short period of time. A“foam”, on the other hand, does not necessarily possess these specificabsorption characteristics and may, for instance, be used for woundclosure, e.g. to prevent infection and/or tissue adhesion, or for tissueregeneration purpose (cell ingrowth into pores). On the other hand, afoam may include such porous structures that are capable of absorbingfluids. Such foams are the subject of the present invention and are alsoreferred to as absorbent foams (including sponges).

The term “packing” as used herein, refers to the action of placing anabsorbent material in a suitable sized form (referred to as packs,tampons, plugs or dressings) in an antrum or other body cavity.

The term “antrum” as used herein, refers to a natural occurring bodycavity, which may also be a lumen.

The term “biodegradable” as used herein, refers to the ability of apolymer to be acted upon biochemically in general by living cells ororganisms or part of these systems, including hydrolysis, and to degradeand disintegrate into chemical or biochemical products.

The term “bioresorbable” as used herein, refers to the ability of beingcompletely metabolized by the human or animal body.

The term “phase-separated polymer” as used herein, refers to a polymercomprising soft (amorphous) segments, as well as hard (crystalline)segments, the hard segment having a phase transition temperature of atleast mammalian body temperatures (which is generally 37° C. for humans)and the phase-separated morphology being manifest when the foam preparedfrom such a polymer is applied in the human or animal body for asufficient period of time. Also, the polymer placed under temperatureconditions comparable to the human or animal body exhibits saidphase-separated morphology. A phase separated polymer is characterisedby the presence of at least two immiscible or partly miscible phaseswith a different morphology at normal environmental conditions. Withinone material a rubber phase and a crystalline phase (at a temperatureabove the glass transition temperature of the amorphous phase and belowthe melting temperature of the crystalline phase) may be present or aglassy and a crystalline phase (at a temperature below the glasstransition temperature of the amorphous phase). Also at least twoamorphous phases can be present at a temperature between the two phasetransitions e.g. one glassy and one rubbery phase. At a temperatureabove the highest phase transition which is either a melting- or glasstransition temperature, the liquid and rubbery or the two rubberyphases, respectively, can form a phase mixed morphology or they canstill be immiscible. Immiscible liquid and/or rubbery phases usuallyresults in a polymer with a phase separated morphology without theinitial desired mechanical properties at normal environmentalconditions.

The term “amorphous” as used herein, refers to segments present in thepolymer of the invention with at least one glass transition temperaturebelow the temperature of the antrums or other cavities of the human oranimal body into which the foam is packed, and may also refer to acombination of an amorphous and crystalline segment which is completelyamorphous when packed in the human or animal body. For example, PEG in apre-polymer may be crystalline in pure form, but may be amorphous whencomprised in the R segment of a polyurethane of the formula (I) or (II).Longer PEG segments may also be partly crystalline when comprised in theR segment of a polyurethane of the formula (I) or (II), but will becomeamorphous (“dissolves”) when placed in contact with water. Thereforesuch longer PEG segments are part of the soft segment of the phaseseparated polymer of the formulas (I) or (II), whereas the hard segmentshould remain crystalline in nature to provide sufficient support to afoam in the wet and packed state for, at least, a certain period oftime.

The term “crystalline” as used herein, refers to segments, present inthe polymer of the invention, that are crystalline when packed in thehuman or animal body, i.e., that have a melting temperature above thetemperature of the antrums or other cavities of the human or animal bodyinto which the foam is packed.

A “hydrophilic segment” as used herein, refers to a segment comprisingat least one, preferably at least two, more preferably at least threehydrophilic groups such as can be provided for instance by C—O—C, orether, linkages. A hydrophilic segment may thus be provided by apolyether segment. A hydrophilic segment may also be provided bypolypeptide, poly(vinyl alcohol), poly(vinylpyrrolidone) orpoly(hydroxymethylmethacrylate). A hydrophilic segment is preferablyderived form polyalkyleneglycol, such as polyethyleneglycol,polypropyleneglycol, or polybutyleneglycol. The preferred hydrophilicsegment is a polyethyleneglycol (PEG) segment.

The term “segment” as used herein, refers to a polymeric structure ofany length. In the art of polymer technology a long polymeric structureis often referred to as a block, whereas a short polymeric structure isoften referred to as a segment. Both these conventional meanings areunderstood to be comprised in the term “segment” as used herein.

The biodegradable absorbent foam according to the present invention hasthe advantage that it does not have to be mechanically removed afterbeing applied to an antrum, such as the nasal cavity, since it degradesover time. The time before the material starts to loose its mechanicalproperties and disintegrates allows to the surrounding tissue to heal.Meanwhile, the tissue is supported and retained in position by a foam ofthe invention due to its mechanical properties and the foam is capableof absorbing considerable amounts of fluid. After a certain period oftime, the foam degrades and disintegrates. In this way damage to thesurrounding tissue is prevented, or only occurs to a very limitedextent.

The characteristics of this foam material are for a large part broughtabout by the nature of the polymeric material from which the foam isprepared. This polymeric material comprises a phase-separated polymerconsisting of an amorphous segment and a crystalline segment. Withoutwishing to be bound by theory, it is believed that this phase-separationof the various soft (amorphous) and hard (crystalline) segmentsattributes to the specific mechanical properties of the foam material,such as its resilience.

A foam of the present invention comprises, i.a. a polymer whereinurethane, urea or amide bonds are provided. These bonds are denotedZ¹-Z⁴ and optionally Q¹ and Q², in the formulas defined hereinabove andconstitute part of the crystalline segment of the polymer of theinvention provided that q≠0. Since these hard, crystalline segments arechemically incompatible with amorphous aliphatic polyesters,polyetheresters, polyethers, polyanhydride or polycarbonates comprisedin the segment R, phase separation in the polymer occurs. The hardsegments crystallize and form strong hydrogen bonds with other hardsegments resulting into physical cross-links.

Furthermore, the biodegradability of the material is accomplished by theprovision of enzymatically cleavable or hydrolysable bonds in a polymerof the invention. For the material to be biodegradable, several types ofpolymers known to the art may thus be comprised in a polymer of theinvention. Such biodegradable polymers may include polymers with one ormore ester, anhydride and/or carbonate hydrolysable moieties, optionallycombined with ether moieties. Such groups are very suitable provided inthe R element according to the formula (I) or (II) for a polymer for usein a foam of the invention, although the ether or ester moieties mayalso be comprised in the R′ and/or R″ elements of the crystallinesegment. In the case that q is zero in polymers of formula (I) or in thecase that there are no hydrogen-bond forming groups present in thecopolymer, e.g. in polymers other than those of formula (I), i.e. suchas in those of the formula (II), the phase separation of crystallinehard segment and amorphous soft segments is provided by incompatiblepolyether, polyester, polyanhydride and/or polycarbonate groups, atleast one phase being crystalline, comprised for example through R informula (I) or otherwise.

The polymers of the invention are believed to degrade by the hydrolysisand/or enzymatic mechanism of the ester, carbonate, anhydride, urethane,urea or amide linkages. The rate of degradation and other properties canbe regulated by choosing the content and combination of these moietiesin the final polymer.

Examples of synthetic biodegradable polymers that can be applied in themanufacturing of foams of the present invention are those based onpolyesters, polyhydroxyacids, polylactones, polyetheresters,polycarbonates, polydioxanones, polyanhydrides, polyurethanes,polyester(ether)urethanes, polyurethane urea, polyamides,polyesteramides, poly-orthoesters, polyaminoacids, polyphosphonates andpolyphosphazenes. The polymeric material may also be composed ofmixtures of above components either as different building blocks of thecopolymer or cross-linked polymer or as a blend of two or more(co)polymers.

For providing the foam material with absorbent characteristics, it hasfurthermore been found that the polymers used for the preparation of thefoams of the present invention can be improved considerably bycombination of the polymer with hydrophilic polymers or groups. Thismeans that the above mentioned polymers are chemically combined withthese hydrophilic groups, e.g. by incorporating hydrophilic polymers inthe backbone or side-chains of the resulting polymers. Also a foam ofthe invention may comprise physical blends of biodegradable andhydrophilic polymers. Hydrophilic polymers or groups may be based onpolyethers, polypeptides, poly(vinyl alcohol), poly(vinylpyrrolidone) orpoly(hydroxymethylmethacrylate) (poly-HEMA). The preferred hydrophilicpolymer is a polyether, viz. a polymer or segment comprising at leastone —C—O—C— group, because these compounds are easy to handle inchemical synthesis reactions. Moreover, these compounds are generallyregarded safe (GRAS). The preferred polyether is polyethyleneglycol. Thehydrophilic groups are part of the soft segment where they will increasethe degradation rate of the ester, carbonate or anhydride groups underthe conditions were the foams of the present invention are to beapplied, and may additionally be part of the hard segment.

In particular the absorption capacity (amount of water uptake and ratethereof) and degradation behaviour can thus be controlled byincorporating during synthesis a suitable quantity of these hydrophilicpolymers or groups. It is thus also possible to incorporate hydrophilicgroups into the hard segment to increase the solubility and/or rate ofdegradation of the hard segment and thus shorten the time needed forcomplete degradation or resorption of the polymer, however, care shouldbe taken that the hard segment provides the phase-separated polymer withsufficient resilience, even when wet.

From the above it is clear that, by proper selection of the soft andhard segments the period of time for biodegradation by enzymes andfluids of the human or animal body can be controlled, as well as theextent to which the material is degraded. Complete biodegradation willresult in fragments that are small enough to be metabolised by the body.In a particular application of the material such as a nasal dressing,the degradation products of this material, in smaller or largerfragments, are cleared either via the digestive channel or via bodilyorifices, such as the nose, nostrils, before they are degraded in tofragments that can be metabolized by the body. An absorbent foamaccording to the invention may suitably comprise polymeric materialsthat are not completely bioresorbable, but only biodegradable to anextent that allows clearance, in smaller or larger fragments, from thecavity where they were applied.

The time until fragmentation of the foam starts (which is the time untilthe mechanical strength of the foam is lost upon putting a slightpressure, although the foam might still show some elastic behaviour) mayvary from a few hours to several weeks but is preferably from 1 hr-21days, more preferably from 6 hrs to 5 days, the preferred time beingdepending on the site and purpose of the application. Completefragmentation (no cohesion of the material and/or foam structure) anddisappearance is preferably from 1-10 days, more preferably from 2-5days in the event that the foam has to be cleared from the wound after atemporary use (e.g. a nasal packing). In case the foam is used in anartificially made cavity such as a dental implant for closing anoro-antral communication or as a haemostatic sponge, the time untilfragmentation starts is preferably within 1 and 14 days. During thistime or afterwards, tissue in-growth in the highly porous foam materialcan take place followed by complete degradation and absorption of thedegradation products by the body. The time until the material iscompletely degraded and absorbed will depend on the type of buildingblocks of the polymer and the rate of hydrolytic and/or enzymaticdegradation thereof. This may vary from several weeks or months to a fewyears.

In the oral cavity, e.g. after tooth extraction, an absorbent foamaccording to the invention may biodegrade more slowly, so as to allowgrowth of new tissue. In dental surgery, for instance, situations mayoccur in which a completely bioresorbable material is required. Forinstance, during extraction of an element of the maxilla, acommunication between the oral cavity and the maxillary sinus may becreated. Such an oro-antral communication is usually closed by asurgical procedure in which a mucosal flap is sutured over the wound.Closure with a bioresorbable foam of the present invention has theadvantage of lower discomfort to the patient. Closure with anbioresorbable foam of the invention protects the maxillary sinus frombeing infected.

Furthermore the absorbent foam absorbs blood by its haemostatic andporous structure and displays sufficient strength to remain properlypositioned during the time of healing of the wound. New tissue may growinto the absorbent foam. After a certain period, which may be controlledby proper selection of the polymer used for its manufacture, thebiodegradable absorbent foam of the invention will degrade to mereresidue and will eventually be completely metabolized by the body.

Such a completely metabolizable absorbent foam pertains to anotheradvantage of the present invention. If the bioresorbable absorbent foamof the invention is applied in the human or animal body (for example ahaemostatic laparotomy sponge or as an implant) and is left in placewithout the intention of ever being removed therefrom, the degradationproducts have to be metabolised by the body. Therefore, polymericmaterial from which an absorbent foam according to the present inventionis prepared is preferably chosen such that it is completelybio-absorbable. Application of such bio-absorbable absorbent foam insurgical intervention has the advantage that the material does notnecessarily have to be removed after surgery, but that it can be left inplace. It is an aspect of the present invention to provide abiodegradable synthetic absorbent foam for use in the human or animalbody.

The materials according to the present invention have the advantage thatthey will disintegrate in a period of time of several days, or atmaximum several weeks. This reduces the incidence of complicationsinduced by the removal of haemostats and increases patient'sconvenience. According to the invention a material is provided havingsuperior mechanical properties, including excellent elasticity andsupport to the surrounding tissue, which is important in stanching theflow of blood and/or keeping the tissue in its position. Yet thematerial is capable of disintegrating rapidly, followed by clearancefrom a body cavity were it is applied. This combination of featurescannot be arrived at by using conventional biodegradable materials ofanimal derived origin. The elastic properties (as well as themaintenance thereof upon application) are required to support the woundsufficiently to arrest bleeding and/or prevent tissue adhesion.

A foam of the present invention may have a density of 0.01-0.2 g/cm³,preferably of 0.02-0.07 g/cm³. Furthermore, a foam of the presentinvention may have a porosity of 85-99%, preferably from 92-98%, evenmore preferably from 95-98%. A foam of the present invention hassufficient fluid absorption capacity at body temperature.

The fluid absorption capacity is mainly determined by the capillaryabsorption of water into the pores, due to the presence of thehydrophilic nature of the polymer and the pore geometry. The pores ofthe foam must be small enough to retain the fluids. The amount of waterabsorbed in a highly porous foam is almost equal for a range ofporosities, since the total pore volume of the foam is hardly affected.This means that the capacity measured in g water/g polymer is dependenton the density of the foam: e.g. doubling of the density from 0.01gram/cm³ to 0.02 gram/cm³ will give half the absorption capacity (g/g).Therefore, the absorption capacity is measured as the amount of water(g) absorbed per volume (cm³), which is preferably 0.5-0.99 g/cm³, morepreferably 0.75-0.97 g/cm³. For example, a hydrophilic polyurethane foamas described in the examples with a density of 0.04 g/cm³ and having aporosity of 96.4% has an absorption capacity of 0.8 g of water per cm³.This is similar to a capacity of 20 grams of water per gram of polymermaterial.

In nose bleeding applications, the uptake of fluids should be very rapidin order to generate some limited pressure in the wound area as to stopthe bleeding. The fully loaded foam should still provide sufficientsupport to the wound tissue.

Within a short period of time the amount of absorbed liquids should bemaximal, preferably within 20 minutes with squeezing of the foam in theliquid. The degree of swelling of the foam should be low: the foampreferably should keep it's dimensions when saturated. A swelling ofless than 10%, preferably less than 5%, more preferably less than 2%should be observed. This is desired in case the foam is pre-wettedbefore insertion of the antrum or cavity. Swelling means in this case,the maximum increase of volume of the foam compared to the volume of adry foam.

A foam of the present invention has mechanical properties such as asufficient resilience or elasticity, which are maintained under “wet”conditions, i.e., when the foam is in contact with bodily fluids,including e.g. purulent material. Both the solubility of the polymerblocks in water and the molecular weight of the polymer are importantfor these aspects as will be elucidated later with some examples.

A foam of the present invention is hydrophilic, viz. shows a goodwettability. A good wettability may be defined as having a contact angle(for water droplets) that is substantially lower than 80°, preferablylower than 40°, more preferably substantially zero degrees.

Preferably, the foam of the invention is provided in one piece, sincethis enables an easy way of manufacturing. However, several pieces canbe used at the same time in order to fill a cavity with sufficientmaterial to absorb the blood and arrest the bleeding. The foam can bemade in any possible shape and size by the use of e.g. casting methodswell known in the art.

The foam of the present invention may be in the form of e.g. plugs(packs, tampons or dressings) or porous sheets. The sheets maysubsequently be rolled into a plug or tube).

A foam for filling a nasal cavity may very suitably have a thickness of1-50 mm, preferably of 8-15 mm, more preferably 12-15 mm. The width ofthe foam is preferably 10-30 mm, more preferably 15-20 mm. Its length istypically several tens of mm, e.g. 20 to 90 mm, or more.

FIG. 1 shows an example of a shape of a foam according to the presentinvention, which can be used e.g. post-surgically as a nasal packing orfor treating of epistaxis, having a thickness (h) of e.g. 10-15 mm; awidth (w) of e.g. 15-20 mm; and a length (1) of 35 to 85 mm. Thedepicted shape and size are preferred for filling a nasal cavity andgive good compression to the mucosal tissue.

According to the present invention foams, suitable for packing antrumsor other cavities of the human or animal body, comprise aphase-separated polymer consisting of an amorphous segment and acrystalline segment and wherein at least the amorphous segment comprisesa hydrophilic segment. According to the present invention the polymer onwhich the absorbent foam is based is a phase-separated linear polymer ora chemically cross-linked polymer.

A phase separated morphology results in a polymer having at least twophase transitions in one polymer as indicated by two meltingtemperatures, two glass transition temperatures or one melting point andone glass transition temperature.

It was found that the above-mentioned requirements can be very suitablyobtained by providing a phase-separated synthetic polymer comprising—C(O)—O— groups in the backbone of the polymer. Preferably the polymeris a polyurethane (—NH—C(O)—O—), polyester (—C(O)—O—), polyanhydride(—C(O)—O—C(O)—) or polycarbonate (—O—C(O)—O—) based polymer, viz. apolymer wherein a nitrogen atom (polyurethane based), carbon atom(polyester or polyanhydride based) or oxygen atom (polycarbonate) isconnected to the C-atom of said —C(O)—O— groups together with either analiphatic carbon atom next to the O-atom (polyurethane, polyester andpolycarbonate) or a carbonyl group (polyanhydride).

The backbone of the polymer used in accordance with the presentinvention is preferably formed of a copolymer, which comprises two ormore different units, at least one selected from the urethane, urea oramide moieties, and at least one selected from the group of ester,anhydride or carbonate moieties combined with an ether moiety.

A very suitable copolymer for application as a hydrophilic biodegradablefoam is a polyether(ester)urethane.

In another preferred embodiment, the foams comprising phase separatedpolyesters, polyanhydrides and combinations thereof with polycarbonateand polyether groups may be either random or block copolymers in which ablock can contain one or more of the above mentioned moieties.Preferably, block copolymers are used, in particular multi-blocksegmented copolymers in which both a crystalline and an amorphous phaseare present. Physical blends of a phase separated polymer with anotherphase separated or a single phase amorphous (co)polymer may be used information of foams with intermediate properties. By varying thecombination of polymers, the foam properties can be tuned such as rateof degradation, hydrophilic and mechanical properties. For example, afoam of a blend of a polyesterurethane and a co-polyester with a similarcomposition as the soft segment of the polyurethane gives propertiesintermediate of those of the two components, due to the compatibility ofthe polymers. Furthermore, poly(ether)esterurethanes with different softsegment composition, the soft segments being either compatible or not,and with the same type of hard segment may be mixed and produced into afoam with intermediate properties.

High molecular weights are not required to obtain a polymer or foam withgood initial mechanical properties. Preferred intrinsic viscosities liebetween 0.5 and 4 dl/g, depending on the type of polymer that is used.For instance, for certain polyurethanes, an intrinsic viscosity of 0.6dl/g can still give a highly porous foam with good mechanicalproperties. Phase-separated polyurethanes according to formula (I) withmolecular weights of the pre-polymer of 2000 may have an initial elasticmodulus varying from 30-120 MPa and a tensile strength of 10-45 MPa. Theelongation at break varies from 500-1200% (measured on polymeric films).

Alternatively, synthetic polymers may be used based on polyamides (viz.polymers containing —NH—C(O)— units in the backbone) or polyurea (viz.polymers containing —NH—C(O)—NH— units in the backbone). Combinations ofurethane, urea and/or amide linkages in the above mentioned structuresare also possible. A very suitable copolymer for application in ahydrophilic biodegradable foam is a polyether(ester)urethane.

The phase separated polymers can be semi-crystalline homopolymers, blockcopolymers or multi-block segmented copolymers. At least one phase haspreferably a transition temperature higher than 37° C. The segment orblock with the highest transition temperature is referred to as the“hard” block, while the segment or block with the lowest transitiontemperature is referred to as the “soft” block. The hard block mayconsist of urethane, urea, amide, polyester or poly-anhydride groups,preferably with a phase transition from a crystalline to liquid state,or a combination of these elements. The soft block preferably comprisesan amorphous polyester, poly-anhydride or poly-carbonate with a glasstransition temperature of 37° C. or below. Such a temperature makes afoam very suitable for use in the human body.

The pliability, compressibility and elasticity of the foam can becontrolled by selecting the ratio between hard and soft blocks as wellas their composition in the polymer. The content and composition of thehard block contributes to the initial strength of the foam in the wetand dry condition. Therefore, the content and composition of the hardblock must be chosen such that sufficient initial strength of the foamin the wet and dry condition is obtained. In order to produce a foam ofwhich the structure is maintained after wetting, the hard blockspreferably has a less hydrophilic character than the soft blocks. Inorder to achieve a faster dissolution of the polymer and rapid loss ofmaterials properties, which is in some cases advantageous, a morehydrophilic hard block may be selected.

A phase-separated polymer according to the invention may be representedby the formula:

—[R-Q¹[—R′—Z¹—[R″—Z²—R′—Z³]_(p)—R″—Z⁴]—R′-Q²]-_(n)  (I),

wherein R, R′, R″, Z¹—Z⁴, Q¹, Q², n, p and q are as defined above.

In this formula, —R— represents the soft segment, or a combination of asoft segment and a hard segment.

Further, the part -Q¹[—R′—Z¹-[R″—Z²—R′—Z³]_(p)—R″—Z⁴]_(q)—R′-Q²represents the crystalline or hard segment, the composition of which islargely determined by the method of manufacturing of this segment of thepolymer (see below). In such a polymer, the bonds are preferably suchthat they provide for the possibility of hydrogen bonding betweenindividual polymer strands. Therefore, Q¹ and Q² are preferably selectedfrom urea, urethane or amide. When q is 0 in this part, i.e. when apolymer of the formula —R-Q¹-R′-Q²- is comprised in a foam of theinvention, the phase-separated morphology is best achieved in thepolymer by providing one crystalline R element together with oneamorphous R element, i.e. by the provision if two different R elements,since the element -Q¹-R′-Q²- itself usually does not provide sufficientcrystalline properties. When q=0 the choice for Q¹ and Q² is lesscritical.

R is selected from one or more aliphatic polyesters, polyetheresters,polyethers, polyanhydrides and/or polycarbonates, and at least one Rcomprises a hydrophilic segment, R′ and R″ are independently C₂-C₈alkylene, optionally substituted with C₁-C₁₀ alkyl or C₁-C₁₀ alkylgroups substituted with protected S, N, P or O moieties and/orcomprising S, N, P or O in the alkylene chain. When no hydrophilicsegment is present in the part of the polymer that is associated withthe aliphatic polyether, polyester, polyanhydride and/or polycarbonate,a suitable biodegradable and hydrophilic polymer for the manufacture ofa foam of the invention may be provided by selecting at least one Relement to be a polyether. Alternatively, the hydrophilic segment mayalso be comprised in the R′ or R″ element, although this is notpreferred. A hydrophilic segment is always present in the soft segment.

The R element, derived form the pre-polymer A-R-A′, may suitablycomprise an amorphous polyester, obtained, for instance, by ring openingpolymerization of cyclic lactones such as lactide (L,D or LID),glycolide, ε-caprolactone, δ-valerolactone, trimethylene carbonate,tetramethylene carbonate, 1,5-dioxepane-2-one or para-dioxanone. Thesepolyester pre-polymers preferably contain hydroxyl end-groups obtainedby using 1,4-butanediol or polyethyleneglycol as an initiator.

R′ is C₂-C₈ alkylene, optionally substituted with C₁-C₁₀ alkyl or C₁-C₁₀alkyl groups substituted with protected S, N, P or O moieties and/orcomprising S, N, P or O in the alkylene chain. R′ is derived from adiisocyanate of the formula O═C═N—R′—N═C═O (formula IV), such asalkanediisocyanate, preferably 1,4-butanediisocyanate (BDI).

R″ is C₂-C₈ alkylene, optionally substituted with C₁-C₁₀ alkyl or C₁-C₁₀alkyl groups substituted with protected S, N, P or O moieties and/orcomprising S, N, P or O in the alkylene chain. R″ is derived from acompound of the formula B—R″—B′ (formula V), wherein B and B′ areindependently selected from hydroxyl, carboxyl or amine, preferably1,4-butanediol (BDO).

Z¹—Z⁴ may be urea, amide or urethane, preferably urethane. In that case,the polymer of formula (I) is a polyurethane. The structure of thepolymer of the invention will be more apparent when understanding themethods for its manufacture. In a phase separated polymer of theinvention, preferably at least 4 hydrogen bond forming groups such asamide, urea and urethane are present in a row in the crystallinesegment. Other bonds (Q¹ and/or Q²) may also be carbonate, ester oranhydride. Therefore, R′ is not necessarily derived from a diisocyanatecomponent such as the compound of the formula (IV). Moreover, the groupR′ in —Z²—R′—Z³— may be different or similar to R′ in -Q¹-R′—Z¹— or—Z⁴—R′-Q²-.

Preferably, in a polymer of the invention, the hard segments have auniform block length. This means that within one polymer according toformula (I), the values for p and q are constant. A uniform block lengthalso implies very good phase-separation and can be obtained by differentchain-extending methods. A phase separated polymer with the highestdegree of phase separation, is i.a. obtained by chain-extending the softsegment forming pre-polymer R (hydroxyl terminated in case R is derivedby ring opening polymerization of cyclic lactones and using a diol asthe initiator) with a diisocyanate chain-extender.

Diisocyanate chain-extenders that are suitable for obtaining polymerswith uniform hard segments and with suitable mechanical properties aree.g. diisocyanate-end-capped diol components, obtained i.a. by reactingone equivalent of an R″ comprising diol, such as 1,4-butanediol (BDO)with two equivalents of the R′-comprising diisocyanate, such as1,4-butanediisocyanate (BDI). This results in a compound of the formula:

O═C═N—R′—Z¹—R″—Z²—R′—N═C═O  (VI)

In the case the diol is 1,4-butanediol (BDO) and the diisocyanate is1,4-butanediisocyanate, this ‘3-block’ chain-extender, or intermediatediisocyanate complex, is named BDI-BDO-BDI and will, when reacted to thecompound of the formula (III), result in a polymer according to theformula (I) wherein p is 0 and q is 1 and the hard segment comprises thesegment sequence R′—R″—R′.

A polyurethane according to formula (I) wherein p is 1 and q is 1, maybe obtained by reacting two equivalents of an R″ comprising diol, suchas 1,4-butanediol (BDO) with one equivalent of the R′-comprisingdiisocyanate, such as 1,4-butanediisocyanate (BDI) and end-capping oneequivalent of the thus formed BDO-BDI-BDO reaction product with twoequivalents of 1,4-butanediisocyanate (BDI). This results in a ‘5-block’chain-extender, or intermediate diisocyanate complex, according to theformula:

O═C═N—R′—Z¹—R″—Z²—R′—Z³—R″—Z⁴—R′—N═C═O  (VIII).

When 4-butanediisocyanate (BDI) and 1,4-butanediol (BDO) are used, thiscompound is shortly addressed with BDI-BDO-BDI-BDO-BDI. Such hard blocksegments provide for phase-separated polyurethane polymers from whichvery advantageous foams can be prepared, i.e. foams with veryadvantageous properties.

A phase-separated polyurethane suitable for preparing a foam of theinvention can also be obtained by a method in which a di-hydroxyterminated pre-polymer is first reacted with an excess of adiisocyanate, resulting in an isocyanate end-capped pre-polymer.Subsequent chain-extension may occur by reacting the isocyanateend-capped pre-polymer with a) a diol compound of the formula (V), orwith b) another intermediate compound, such as can for example beobtained by reacting one equivalent of a diisocyanate according to theformula (IV) with two equivalents of a diol of the formula (V), toprepare a compound of the formula:

B—R″—Z¹—R′—Z²—R″B′  (VII).

An example of such a compound (VII) is the reaction product BDO-BDI-BDO.

Reacting the isocyanate end-capped pre-polymer with the compound of theformula (VII) will result in a phase-separated polyurethane of uniformblock length and with p=1 and q=1, whereas the direct chain extension ofthe isocyanate end-capped pre-polymer with a diol compound of theformula (V) will result in a phase-separated polyurethane of uniformblock length wherein and p=0 and q=1.

The degree of phase separation may in some cases be somewhat lower thanis obtained by the chain-extension method described hereinabove, whereinthe pre-polymer is not end-capped. I.e. performing a reaction between apre-polymer and a diisocyanate and chain extending with e.g. a diolaccording to the formula (V) results in a polymer wherein thephase-separated is sub optimal to that of a polymer obtained by reactinga diisocyanate-end-capped chain extender with a pre-polymer according tothe formula (III). The degree of phase-separation may be lower in thepolymers that are obtained by reacting the diol component according tothe formula (V) as the chain-extender. A diol according to the formula(V) can cause trans-esterification of the labile ester groups of thepre-polymer so that the uniformity of the hard block is lost. Thesensitivity of the ester group towards trans-esterification is verydependent on the chemical environment of this group. For instance, estergroups in poly-(lactide) segments are much more labile than ester groupsfrom poly(caprolactone) segments. Consequently, polyurethanes based onpoly-(lactide) segments will have a less phase separated structure thanthose based on poly(caprolactone) segments. A diisocyanatechain-extender does not cause this side-reaction, resulting in an evenbetter phase-separation.

A method for preparing a phase-separated biodegradable polymer accordingto the invention, thus comprises the steps of reacting one or morepre-polymers of the formula:

A-R-A′  (III),

with one or more diisocyanates of the formula:

O═C═N—R′—N═C═O  (IV)

and optionally one or more chain extenders of the formula:

B—R″—B′  (V)

wherein R, R′ and R″ are as defined in formula (I), and A, A′, B and B′are independently selected from hydroxyl, carboxyl or amine. Preferable,the above compounds (III), (IV) and (V) are reacted in a solvent, morepreferably in 1,4-dioxane or trioxane.

The reaction between the pre-polymer of the formula (III) end-cappedwith the diisocyanate of the formula (IV) and the chain extender offormula (V), or the reaction between either one of the intermediatediisocyanate complexes described above and the pre-polymer of theformula (III) is generally carried out at a temperature between 15° C.and 90° C., preferably between 55° C. and 75° C., more preferablybetween 60° C. and 70° C.

The polymer of the present invention may be produced in bulk, or, morepreferably, it may be produced in a solvent. A very suitable suchsolvent is 1,4-dioxane or trioxane. 1,4-Dioxane is the preferred solventsince it is advantageously cheap. Preferably, the pre-polymer anddiisocyanates are reacted in bulk, whereas the chain extending reactionis preferably performed in 1,4-dioxane.

The initial rate of degradation of the foam depends on the compositionof the polymer soft segment; the initial molecular weight (obtained bymeasuring the intrinsic viscosity) as well as the composition determinethe time between the start of the gradual fragmentation and the loss ofmechanical properties. Excellent results have been obtained using apolyurethane of formula (I) with p=1 and q=1, and R′ and R″ both being(—CH₂—)₄. As aliphatic polyethers, polyesters, polyanhydrides and/orpolycarbonates for use in a polymer of the present invention, anycompounds may be employed. Preferably, R is a pre-polymer containing anamorphous polyester, obtained by ring opening polymerisation of cycliclactones such as lactide (L,D or LID), glycolide, ε-caprolactone,δ-valerolactone, trimethylene carbonate, tetramethylenecarbonate,1,5-dioxepane-2-one or para-dioxanone and mixtures thereof. Mostpreferably, the pre-polymer is a combination of lactide andε-caprolactone and with a molecular weight of 2000. The monomer ratio issuch that the poly(caprolactone) sequences do not crystallise.Preferably, the ε-caprolactone content is less than 60%, more preferablybetween 30 and 60%, most preferably it is about 50%. The polyester iscombined with polyethyleneglycol in a weight content of 1-80%,preferably 5-60%, more preferably 20-50%, most preferably about 50%. Itis preferred that the polyethyleneglycol is present as an initiator ofthe pre-polymer.

Very suitable foams can be produced from polymers wherein R is anamorphous polyester derived from lactide and ε-caprolactone, with amolecular weight between 1 000 and 4 000 and even more preferably frompolymers wherein said amorphous polyester comprises about 25 wt. %lactide, about 25 wt. % ε-caprolactone and about 50 wt. % ofpolyethyleneglycol.

The molecular weight of the pre-polymer is preferably about 1500-2000.This may be obtained by using a diol, e.g. 1,4-butanediol as aninitiator or a polyethyleneglycol (PEG) with molecular weight of 1000.The first obtained pre-polymer may then combined with the desired amountof PEG as a second pre-polymer. The PEG initiated pre-polymer alreadycontains at least 50% (w/w) PEG and can also be mixed with anotherpre-polymer or PEG to adjust the total amount of PEG in the pre-polymer.

The polymerization reaction between the two types of pre-polymers asemployed in a method of the invention for preparing an absorbent foammay comprise such reactions as known in the art. Polyesters,polycarbonates, polyamides or polyanhydrides can be made by methods suchas ring opening polymerisation and/or condensation reactions, followedby the chain-extending (or polymerization) process. Polyurethanes mayfor instance be made by a condensation reaction of isocyanates withhydroxyl groups, by means of chain-extending of pre-polymers. Polyureaare made by a similar condensation of an isocyanate with an amine group.

Alternatively, different pre-polymers and chain extenders can be coupledby reaction of activated functional groups (such as carboxylic acid,hydroxyl or amine). Several methods for activating functional groups areknown in the art. Examples are the uses of N-hydroxysuccinimide andderivatives, carbonyldiimidazole, aldehydes, maleimides, dicycloxexylcarbodiimide (DCC). The advantage of the use of such coupling agents isthat high temperatures that are usually applied in condensationreactions are avoided. Therefore, in another embodiment of theinvention, a foam may be prepared by a method comprising preparing aphase-separated biodegradable polymer of the formula (II) by reacting amixture of at least two compounds according to formula (III), of whichat least a first such compound comprises an R group representing anamorphous segment comprising a hydrophilic segment, and of which atleast a second such compound comprises an R group representing acrystalline segment, said method further comprising providing saidmixture with a compound of the formula (V) and performing a chainextension reaction between said compounds in the presence of anactivator such as N-hydroxysuccinimide or derivatives,carbonyldiimidazole, aldehydes, maleimides or dicycloxexyl carbodiimide(DCC).

Alternatively, a foam may be prepared by a method comprising preparing aphase-separated biodegradable polymer of the formula (II) by reacting amixture of at least two compounds according to formula (III), of whichat least a first such compound comprises an R group representing anamorphous segment comprising a hydrophilic segment, and of which atleast a second such compound comprises an R group representing acrystalline segment and performing a chain extension reaction in thepresence of an activator such as N-hydroxysuccinimide or derivatives,carbonyldiimidazole, aldehydes, maleimides or dicycloxexyl carbodiimide(DCC). Such extension reactions in the presence of an activator are wellknown in the art.

Because the presence of an R′ or R″ group is not necessary in a polymersuitable for the manufacture of a foam of the invention, two differentpre-polymers according to the formula III (comprising R groups) may thusbe joint together directly. The provision is that at least one R groupis amorphous and one R group is crystalline. The joining together ofsuch pre-polymers may be achieved by providing such compounds in theform of diols or dicarboxylic acids as described earlier. However, whenthe presence of isocyanates is, for instance, to be avoided in areaction mixture or the presence of urethanes in a polymer of theinvention is to be reduced, use of a diisocyanate according to theformula (IV) may be prevented by coupling the pre-polymers comprising anR group by alternative methods.

A very suitable alternative method may comprise the use of so calledactivators like N-hydroxysuccinimide, carbonyldiimidazole, aldehyde,maleimide or dicycloxexyl carbodiimide (DCC) or derivatives thereof.Such activators are capable of chemically bonding pre-polymerscomprising an R group that are similar to the compounds of the formula(III), to form a polymer of the formula (II), wherein Q¹ or Q² maycomprise different groups as described. Q¹ or Q² carbonate groups may,for instance, be created in the polymer of the formula (II) byperforming a condensation-reaction with phosgene. Q¹ or Q² anhydridegroups may be introduced by performing a coupling-reaction betweencarboxylic acid end-groups of such pre-polymers.

Therefore, a polymer according to the formula (I) or (II) may alsosuitably be performed by using coupling reactions with activators,instead of reactions involving, for example, diols and diisocyanates ina method of the invention described earlier. The Q¹ and Q² groups maysuitably be prepared as an ester, an anhydride or a carbonate byselecting the chain extender and the pre-polymer such that theirterminal reactive groups comprise the proper combination of for example,carboxylic acid, alcohol or chlorocarbonate groups (e.g. a compound ofthe formula (III) Cl—(CO)—O—R—). Thus, in alternative methods forpreparing a polymer of the invention for the manufacturing of a foam ofthe invention, a compound of the formula (III) may be coupled or reactedwith another compound of the formula (III) in the presence of anactivator, provided that one compound is amorphous and one iscrystalline. Also, a compound of the formula (III) may be coupled orreacted with another compound of the formula (III) in the presence of acompound of the formula (IV), in which case no activator is necessary,since the isocyanate will provide the necessary energy. Also, a compoundof the formula (III) may be coupled or reacted with another compound ofthe formula (III) in the presence of a compound of the formula (V), inwhich case an activator is again necessary. The skilled person willunderstand what alternative methods and building blocks may be used toarrive at the phase-separated polymers suitable for the manufacturing offoams according to the present invention.

Foam material according to the present invention is preferably preparedby a freeze-drying process. As stated, the advantage of producing apolymer of the present invention in a solvent is that a veryadvantageous starting material is thus provided for the preparation of afoam of the invention. A very suitable route of preparation comprisesproducing the polymer in a suitable solvent, followed by cooling, duringwhich cooling step the polymeric material precipitates or crystallizesand the solvent crystallizes, and finally a freeze-drying step. In thisrespect it is noted that 1,4-dioxane is a very suitable solvent. Bypreparing the polymer in the solvent, the process step of dissolving thepolymer in the solvent may be avoided and a very efficient manufacturingprocess for biodegradable absorbent foams according to the presentinvention is thereby obtained.

By using a freeze drying method, the foam can be made directly from thepolymer solution, which simplifies the process (isolation of the polymerby precipitation from the solution is not necessary). In casemulti-functional chain-extenders or pre-polymers are used (more than 2reactive groups) the cross-linking reaction can take place in solutionin the mould, after which the solvent is frozen and sublimated.Furthermore, the porosity of the foam can easily be changed. By additionof non-solvents, the foam structure and homogeneity can be tuned. Thesolvent can be completely removed, i.e. so that residual content islower than acceptable limit, by freeze drying.

It is preferred to carry out the polymerisation reaction either in thebulk or in a 1,4-dioxane solution. Usually in the art, polyurethanechain-extending reactions are carried out in very polar solvents such asdimethyl sulfoxide (DMSO), N-methylpyrrolidone (NMP) ordimethylformamide (DMF) examples of which are given in internationalpatent nr. WO99/64491. Polar solvents are mainly used because of thevery good solubility properties of polyurethanes and other hydrogen-bondforming polymers in these solvents. In this way, high molecular weightscan be obtained. Applying these solvents, requires an additionalprecipitation step of the polymer solution in a non-solvent such aswater. Except for the fact that it is a time consuming step, it is alsoa disadvantage that the polymers have to be dried afterwards which mightlead to early degradation or cross-linking reactions of the polymer.Furthermore, not all polymers are hydrolytically stable in this type ofsolvents. In case a (very) hydrophilic polymer is made (as is the casewith some of the polymers of this invention), a precipitation step intowater is undesirable. The polymer will swell and may be difficult toisolate and dry without some degradation taking place.

Using 1,4-dioxane as a solvent offers many advantages: polymers withsufficient molecular weight are being formed; the polymerisationtemperature and polymerisation time can generally be lower, which maylead to less side-reactions (e.g. trans-esterification) and a betterphase separation; the initial pre-polymer concentration can be muchlower than in e.g. DMSO (35% vs. 60% w/w), which makes the processbetter to control (e.g. viscosity of a solution can easily bemonitored); foams of polymer networks can be made, the polymer solutioncan be diluted to the desired concentration after which the solution canbe poured directly into the mould, frozen and freeze dried. If desired,the dioxane solution can be precipitated into water or organicnon-solvents. Furthermore, polymer solutions in dioxane can be easilyformed into solid materials such as polymeric films and sheets byevaporation of the solvent at rather low temperatures.

In another process for preparing a foam suitable for packing antrums orother cavities of the human or animal body, the synthesis of the polymeris performed in the bulk and the foam is formed in situ upon formationof carbon dioxide by a chain-extending reaction of a diisocyanatemolecule with a dicarboxylic acid or hydroxycarboxylic acid moleculeand/or water, optionally in combination with reaction of a diol molecule(either a diol pre-polymer or diol chain-extender) to control the amountof liberated gas. This solvent-free method has been described in EP-A-1138 336, but highly porous foams used as an absorbent dressing have notbeen disclosed.

Solvent-free produced foams based on poly(ether)ester urethanes offormula (I) can be obtained by reaction of a diisocyanate chain-extendergroup with a di-carboxylic acid or hydroxycarboxylic acid initiatedpre-polymer optionally combined with a diol initiated pre-polymer orpolyethyleneglycol.

In another method, the biodegradable soft segment is end-capped with1,4-diisocyanate and the di-carboxylic acid or hydroxycarboxylic acidmolecule, a diol and/or water are the chain-extenders.

As stated earlier, foamed materials according to the present inventionare preferably prepared by a freeze-drying process. An alternativemethod comprises the extrusion of porous sheet using a foaming agentsuch as low boiling liquids, solids or carbon dioxide. Such a methodcomprises providing a phase-separated biodegradable polymer and formingsaid polymer into a foam of the invention, for example, by using ablowing agent in a extrusion method as known in the art. Such anextrusion method may for instance comprise the melting of said polymerand the extrusion of the melt thus formed into a foam by the aid of agas, preferably a gas such as carbon dioxide.

The foams manufactured by methods of the present invention may besterilized e.g. with ethylene oxide without loss of shape or volume andwithout significant decrease in molecular weight. The foams may beimpregnated with various substances, that can be released at acontrolled rate upon wetting, which can make these foams also suitablefor drug delivery purposes. Furthermore, loading with radiopaque fillersand haemostatic components is also possible.

The foams of the present invention are characterised by having suitableelastic properties such as needed for application as wound dressingapplications or other biomedical foam uses in accordance with thepresent invention. A foam of the invention can very suitably be used asa haemostatic sponge, such as a laparotomy sponge. Also, it may be usedas a nasal dressing for the treatment of epistaxis, as a dressing forthe outer ear and as a post surgery wound dressing to prevent fromtissue adhesion.

Alternatively, due to its biodegradability and optionallybio-resorbability, a foam of the invention may be used for drug deliverypurposes.

A foam of the invention is very suitable for use in dental surgery andfor closing an oro-antral communication after tooth extraction.Therefore in another aspect, the present invention relates to the use ofa foam according to the invention as a haemostatic sponge, as a wounddressing material, as a packing for antrums or other cavities of thehuman or animal body or as a drug delivery vehicle.

In a final aspect, the present invention relates to the use of aphase-separated biodegradable polymer according to the invention, forthe manufacture of a foam according to the invention.

The invention will now be exemplified by the following, non-limitingexamples.

EXAMPLES Analysis Methods and Characterization of Polymers and BuildingBlocks

The following analysis methods were used in all examples, unlessindicated otherwise.

The intrinsic viscosity was measured in chloroform or 1,4-dioxane at 25°C. using an Ubbelohde viscometer (according to ISO standard 1628-1).Monomer conversion, pre-polymer and chain-extender composition weredetermined using ¹H-NMR at 300 MHz in solutions in deuteratedchloroform.

Thermal properties were determined using a TA Instruments-Q1000 MDSC,5-10 mg samples being heated at a rate of 10° C. per minute, cooled downat a rate of 20° C. per minute and heated again at a rate of 10° C. perminute.

Mechanical properties were determined on thin films with an Instron 4301tensile tester. The films were measured at room temperature at acrosshead speed of 10 mm/minute. The ultimate tensile strength, theelongation at break and the initial modulus were determined from thesemeasurements.

Purification and/or drying of monomers and glassware is according topreviously published methods and is sufficient to obtain polymers withthe desired properties.

Porosities were calculated by measuring the dimensions and the dryweight of a foam, assuming a density of the polyurethane of 1.1 g/cm³.

The absorption capacity of a foam was measured by calculating thewet/dry ratio of a foam after exposing to an excess of water (with orwithout squeezing/soaking of the foam) as a function of time at 37° C.

The degree of swelling was calculated by measuring the dimensions of thefoam before and after saturation with water as a function of time.

Example 1 (50/50) Glycolide-ε-Caprolactone Pre-Polymer (Mn=2000)

The pre-polymer was synthesized by ring opening polymerization ofε-caprolactone and glycolide in a 50/50 (mol/mol) ratio using1,4-butanediol as initiator and stannous octoate as catalyst(M/I=10000). After reaction at 130° C. for 6 days, ¹H-NMR shows completemonomer conversion. Thermal analysis shows a completely amorphouspre-polymer with a glass transition temperature between −40 and −35° C.

Example 2 (50/50 Glycolide-ε-Caprolactone) Pre-Polymer Initiated withPEG1000 (Mn=2000)

The pre-polymer was synthesized by ring opening polymerization ofε-caprolactone and glycolide in a 50/50 (mol/mol) ratio usingpolyethyleneglycol (PEG) with a molecular weight of 1000 as initiatorand stannous octoate as catalyst (M/I=10000). PEG is dried under vacuumat 50° C. during at least 8 hours, where after the monomers and catalystare added. The mixture is reacted at 140° C. for 6 days, ¹H-NMR showscomplete monomer conversion. Thermal analysis shows a semi-crystallinepre-polymer with a glass transition temperature between −50° C. and −40°C., a crystallisation peak between −10° C. and 0° C. and a melting peakof the PEG segment of 15-20° C.

Example 3 (20/40/40) Lactide-Glycolide-ε-Caprolactone Pre-Polymer(Mn=2000)

The pre-polymer was synthesized according to the method of example 1 byring opening polymerization of ε-caprolactone, glycolide and lactide ina 40/40/20 (mol/mo/mol) ratio using 1,4-butanediol as initiator andstannous octoate as catalyst (M/I=10000). Thermal analysis shows acompletely amorphous pre-polymer with a glass transition temperaturebetween −22° C. and −23° C.

Example 4 (20/40/40 Lactide-Glycolide-ε-Caprolactone) Pre-PolymerInitiated with PEG1000 (Mn=2000)

The pre-polymer was synthesized according to the method of example 2 byring opening polymerization of ε-caprolactone, glycolide and lactide ina 40/40/20 (mol/mol/mol) ratio using polyethyleneglycol (PEG) with amolecular weight of 1000 as initiator and stannous octoate as catalyst(M/I=10000). Thermal analysis shows a semi-crystalline pre-polymer witha glass transition temperature of −44° C., and a small melting peak ofthe PEG segment of 22° C. In the second DSC run, the Tg is −47° C., acrystallisation peak at −15° C. and a melting peak at 23° C. areobserved.

Example 5 (50/50 Lactide-ε-Caprolactone) Pre-Polymer Initiated withPEG1000 (Mn=2000)

The pre-polymer was synthesized by the same method as described inexample 2 by using DL-Lactide instead of glycolide. Stannous octoate wasused as a catalyst (MA=10000-15000). The mixture is reacted at 140° C.for 14 days, after which ¹H-NMR shows complete monomer conversion.

Example 6 Synthesis of (3/1) ((50/50)Glycolide-ε-Caprolactone)/PEG1000(w/w) Based Polyurethane with BDI.BDO.BDI.BDO.BDI Hard Segment in1,4-Dioxane

The BDOBDIBDO chain-extender was prepared according to the method givenin international application PCT/NL99/00352 and was subsequentlypurified, such that a purity of 98% was obtained. The melting point ofthe chain-extender was 97° C. In the first step of the polyurethanesynthesis, the hydroxyl terminated pre-polymers of example 1 and 2 in a1:1 molar ratio is end-capped with a 5 to 6 fold excess of1,4-butanediisocyanate (BDI) under mechanical stirring. After reactionat 62° C. for 4 hours, the excess BDI was removed by distillation underreduced pressure (1*10⁻³ mbar) at 65° C. until the theoretical molecularweight of the end-capped pre-polymer is reached.

In the next step of the polymerization, the thus obtainedmacro-diisocyanate pre-polymer is chain extended at 65° C. with theBDO-BDI-BDO chain extender using 1,4-dioxane as solvent (35% w/w). Thechain-extender is added in small portions to the well stirredpre-polymer solution. When the solution becomes viscous, the mixture isdiluted with small amounts of 1,4-dioxane. This procedure is repeateduntil no increase of viscosity is observed. The polymer solution isdiluted to the desired concentration with 1,4-dioxane. A small amount ofwater or c-hexane is added. The solution can be precipitated into wateror organic solvents, it can be concentrated by evaporation of thesolvent and be dried in vacuum or it can be frozen and subsequentlyfreeze dried. An intrinsic viscosity of a freeze dried polymer between 1and 2 dl/g can easily be obtained under these conditions, althoughpolymers with lower molecular weight might be useful for someapplications.

Example 7 Synthesis of (3/1)((20/40/40)Lactide-Glycolide-ε-Caprolactone)/PEG1000 (w/w) BasedPolyurethane with BDI.BDO.BDI.BDO.BDI Hard Segment in 1,4-Dioxane

A polymerisation reaction according to the method of example 6 withpre-polymers of examples 3 and 4 gives a polymer with similar molecularweights.

Example 8 Synthesis of (1/1) ((50/50)Lactide-ε-Caprolactone)/PEG1000(w/w) Based Polyurethane with BDI.BDO.BDI.BDO.BDI Hard Segment in1,4-Dioxane

A polymerisation reaction according to the method of example 6 with apre-polymer of example 5 gives a polymer with similar molecular weights.

Example 9 Preparation of Glycolide Based Foams

The polymer solution of Example 6 is diluted to 2.5 wt. % in dioxane(gram of polymer in polymer/solvent mixture) and 2 wt. % of water (gramof water/gram of solution) is added. The solution is filtered over a 3μm filter and poured into a mould. The solution is frozen at −20° C.after which it is freeze dried at a pressure of 3 mbar, followed bydrying at 1*10⁻³ mbar until constant weight. The foams can be sterilizedwith ethyleneoxide. By the same method, foams of polymer of example 7can be produced. The foams are stored below 4° C. The calculatedporosity of the foams prepared this way has an average of 96.4%.

Example 10 Preparation of Lactide Based Foams

The polymer solution of Example 8 is diluted to 1.8 wt. % in dioxane(gram of polymer in polymer/solvent mixture) and 2 wt. % of c-hexane(gram of water/gram of solution) is added. The solution is filtered overa 3 μm filter and poured into a mould. The solution is frozen at −20° C.after which it is freeze dried at a pressure of 3 mbar, followed bydrying at 1*10⁻³ mbar until constant weight. The foams can be sterilizedwith ethyleneoxide. The foams are stored below 4° C. The calculatedporosity of the foams prepared this way has an average of 97.2%. By thesame method, foams of 3.5 wt. % can be produced with an average porosityof 95%. The foams of this example are particularly useful as a nasaldressing.

Results and Discussion

Thermal, mechanical, absorption and degradation behavior of polymers ofexamples 6 and 7 and foams thereof are determined.

Upon EtO sterilization, the intrinsic viscosity of foams may decreasewith about 0.1 dl/g, while the shape and dimensions of the foams areretained. FIG. 2 shows the thermal behavior of polyurethane foams beforeand after sterilization. The thermal properties are changed somewhat(shift of phase transitions) as a result of annealing of the polymerduring the sterilization process at 40-50° C. (3-4 days in total). Thehard segment gives a broad melting peak, which is caused by a complexformed by the hydrogen atoms of the urethane segments and the ethergroups of PEG.

A porosity of the foam of 96.4% is calculated, which is about 1% lessthan the theoretical calculated porosity based on the 2.5 wt % solution(97.7%). This is mainly due to some shrinkage of the foam during freezedrying. Mechanical properties of the polymer are measured on thin films.To this end, the foams of example 9 made of polymers of example 6 and 7are dissolved in chloroform and the solution is poured into apetri-dish. After evaporation of the solvent and drying in vacuum at 40°C., a transparent film is obtained. The results are shown in Table 1.The difference in strength may be explained by a lower molecular weightof the lactide containing polymer. Mechanical properties of the foamsare not measured quantitatively, but their very good elastic propertiescan be related to the materials properties measured on films.

TABLE 1 Mechanical properties of PEG containing PU's with differentpre-polymer composition Gly/lac/cap ratio 50/0/50 40/20/40 Modulus (MPa)57 67 Tensile strength(MPa) 18 12 Strain at break (%) 750 520

Table 2 shows the absorption capacity and the swelling behavior of foamsof polymers of examples 6 and 7. The tested foams are cylindrical shapedwith a weight of about 100 mg and a porosity of 96.4% (based on a 2.5 wt% solution in dioxane). The foams are soaked in a Sorenson buffersolution (pH=7.4) at 37° C. and left there for 2 weeks. Immediatelyafter soaking (by repetitive squeezing of the foam in the liquid) themaximum amount of water is absorbed (measured after 10 minutes). Thefoam absorbs 20-24 times its own weight and is independent of the sizeand shape of the foam.

After 14 days, the foam has not collapsed, but upon shaking, the foamfragmentizes into small particles. The dimensions of the foam are hardlychanged during the time exposed to the buffer solution. An irregularchange of dimensions during 14 days (measured as the change of diameterof the foam) is observed as a result of inaccurate measurements.Overall, the dimensions of the wet foam are increased with less than 3%compared to the dry foam. For comparison, the absorption capacity ofSpongostan®, a gelatin based wound dressing, is 40 times its dry weight.However, the material swells and looses its mechanical strength almostimmediately.

FIG. 3 shows the water absorption capacity of a foam with the shape anddimensions of FIG. 1 at 37° C. and without soaking the foam. Theporosity is the same as the foams of Table 2 and its weight is about 700mg. It takes about 5 hours until the absorption is leveling of to avalue of 20 times the dry weight of the foams, which is a much longertime than when the foam is squeezed in the liquid. The absorptionbehavior is determined completely by the hydrophilic and capillaryproperties of the foam. The actual use of the foam (e.g. as a nasaldressing) will require compression of the foam to insert it into thewound. Therefore, the initial absorption capacity as shown in Table 2will be most important. Similar absorption tests carried out at 21° C.gives a comparable rate of absorption, which might be important if thefoam is pre-wetted before use.

An in vitro degradation study of foams of polymers of example 6 and 7with a 96.4% porosity have been carried out during a period of 14 days.During this time, the absorption behavior, the change of molecularweight and the change of mechanical properties were measured as afunction of time. The absorption behavior has already been discussed.The intrinsic viscosity is initially decreasing very rapidly. In 3-5hours the intrinsic viscosity is dropped with about 50% of the initialvalue; after that it is leveling of to an almost constant value. This isa result of chain scission in the polyester pre-polymer, caused by thepresence of hydrophilic ether moieties. FIG. 4 shows the decrease of theintrinsic viscosity as a function of time of the two PU foams of example9, and that of the lactide based foam with a 97.3% porosity andcontaining 50% PEG in the pre-polymer of example 10. The replacement ofpart of the glycolide and caprolactone by lactide does not have a largeinfluence on the degradation behavior. The presence of 50% PEG insteadof 25% PEG in the pre-polymer and/or the replacement of all glycolide bylactide seems to increase the initial degradation rate. Within one hour,the intrinsic viscosity has dropped to about ⅓ of the initial value. Thetime until fragmentation of the lactide foams starts is thereforesomewhat shorter than that of the glycolide based foams. The very fastdegradation of these foams is possibly also the result of the weak esterlinkage between the PEG segment and the lactide derived monomer. Theinitial rate of degradation is in general somewhat lower for sterilefoams with a similar composition; after 6-8 hours the intrinsicviscosity is half of the initial value.

Mechanical properties of the degrading foams are changing with the lossof molecular weight. For the PU foams of FIG. 4, the tear strength islost at an intrinsic viscosity of about 0.4-0.5 dl/g. In case the foamsare sterile, it takes a longer time until this point is arrived.Although the foam can be torn into pieces, the foams are still elastic.This means that even a partly degraded foam can put sufficient pressureon a wound to stop the bleeding of the wound or to prevent re-opening ofthe wound. After 1 day in a buffer solution at 37° C., the foam isfragmented under pressure and shaking. The foams of example 10 are verysuitable for using in an application were a fast degradation andclearance of the foam is required such as a treating of epistaxis.

In general, the rate of degradation may be slowed down by choosingmonomers that are more hydrolytically stable than glycolide and lactide.Also the amount of hydrophilic polymer and the way of incorporating inthe polymer can have a large effect on the degradation properties. Thepresence of slowly degrading hard segments is, however, necessary tomaintain the mechanical properties during application in a wound, whichcan be obtained with the polymers of the present invention.

Very suitable polyesters for use in the amorphous (R) segment of thepolymer are based on lactide, glycolide and ε-caprolactone, preferablywith a molecular weight of around 2000. Alternatively, the pre-polymercan be entirely based on lactide and ε-caprolactone. In such analternative, the preferred ratio of the lactide and ε-caprolactone isabout 1 mole/mole. Very favorable results have been obtained with suchcombinations wherein an amount of PEG of about 50 wt. % was provided asa pre-polymer initiator.

Very suitable polyethyleneglycol molecules for use in the presentinvention are those with a molecular weight of 150 to 4000 g/mol.Preferably, the molecular weight is between 600 and 2000 g/mol.

The polyethyleneglycol molecules can be incorporated into the amorphoussegment pre-polymer in any suitable way, for example by ring-openingpolymerization of cyclic monomers using polyethyleneglycol as aninitiator or as a second pre-polymer combined with a polyesterpre-polymer.

Polyethyleneglycol may thus be incorporated into the amorphous segment,to yield amorphous segment with between 1-80 wt. %, more preferably10-60 wt. %, even more preferably 20-50 wt. % of polyethyleneglycol.

A foam of the invention may be loaded with radiopaque fillers in orderto trace the material in the body.

Characteristically, a foam of the invention has a density of 0.01-0.2g/cm³, preferably of 0.02-0.07 g/cm³. The porosity of the foam maysuitably range form 85-99%, preferably from 92-98%, more preferably from95-98%.

The absorption capacity of a foam of the invention at ambienttemperatures (RT−37° C.) is in the range of 0.5-0.99 g/cm³, morepreferably 0.75-0.97 g/cm³.

Generally, upon absorbing aqueous liquids, the biomedical foams of theprior art will rapidly loose either strength or elasticity. The foam ofthe present invention, however, exhibits a high mechanical strength whenfully saturated with water at 37° C. as well as a maintained elasticityand shape. By selecting the type of polymer, the period during which themechanical strength is maintained may be controlled. Preferably, themechanical strength is eventually lost by the action of aqueous liquidson the foam. The fragmentation may however be delayed for a period ofbetween 1 hr and 14 days, preferably between 6 hrs and 5 days. Rapiddisintegration of a foam of the invention may be realized by using apolymer based on glycolide and lactide in combination with relativelyhigh amounts of PEG, whereas disintegration may be for example bedelayed by using monomers such as trimethylene carbonate andcaprolactone, or reducing the amount of PEG in a glycolide/lactide basedpolymer. FIG. 5 shows the time until fragmentation vs the intrinsicviscosity of 1.8% (wt) foams, based on (1/1)((50/50)lactide-ε-caprolactone)/PEG1000 (w/w) in a buffer solution at37° C. upon action of a weight of 50 grams. The higher the intrinsicviscosity, the longer it takes until the foam starts to tear andfragment. Within one hour, the foams starts to fragment, which is muchfaster than foams based on glycolide-ε-caprolactone pre-polymers with25% (w/w) PEG: 15-45 minutes vs 2-3.5 hrs, respectively, for comparableintrinsic viscosities. Foams of less than 1.5% (wt) polymer arefragmenting much faster than those of higher polymer concentration, thetime also being dependent on the initial intrinsic viscosity. Thisproves that the mechanical and physical properties can be tuned by thepolymer composition, content of hydrophilic component, initial intrinsicviscosity, foam porosity and also the mechanical force which is appliedon the foam.

A foam according to the present invention may very suitably have aninitial intrinsic viscosity of 0.5-4.0 dl/g. Generally, the loss ofmechanical strength in the wet state is attained at an intrinsicviscosity of 0.4-0.5 dl/g, but may depend on the foam porosity. A foamof the present invention may comprise a physical blend of a hydrophilicphase-separated polymer with other biomedical biodegradable polymers. Avery suitable polymer for the manufacture of a foam of the inventioncomprises a polyesterurethane combined with a an amorphous single phase(co)polyester or another polyesterurethane.

The foam of the present invention may be in the form of a plug (packs,tampons or dressings) or a sheet, said sheet preferably having athickness of 1-50 mm, more preferably of 8-15 mm.

The foam of the invention may very suitably be used as a haemostaticsponge, such as a laparotomy sponge. Also, it may be used as a nasaldressing for the treatment of epistaxis, as a packing for the outer earor as a post surgery wound dressing.

Due to its high absorption capacity and its controllable degradabilityby delayed disintegration, the foam of the invention may be used fordrug delivery purposes. Preferably, a foam of the invention is used toprevent tissue adhesion. Also very suitable applications have been foundin dental surgery, and specifically for closing an oroantralcommunication after tooth extraction.

Foams of the present invention were studied in a clinical trial in orderto assess their properties as a synthetic fragmentable nasal dressing.

Patients with bilateral sinusitis or polyposis were randomized to leftor right application of the fragmentable dressing (8×1.5×2 cm), thecontra lateral nasal cavity received a standard dressing. Thefragmentable dressings fragmented within 6 days whereafter they weredrained via the mucus flow. Patients were recruited by 3 Dutch centres.25 patients (54% male) were included, with a mean age of 47 years. In71% of the cases it was the first clinical intervention for thepathology. 50% of the patients received medication after the procedure.

The patients experienced discomfort when the durable dressing wasremoved which was not the case with the fragmentable dressing (FIG. 6).Final wound healing at 10 and 30 days was good and comparable betweenthe groups. In 20% of the cases nose bleedings were observed at thecontrol side, zero at the side with the new dressing (FIG. 7). Theseresults indicate that the use of the new fragmentable nasal dressing isefficient and increases the comfort for the patient and lowers the riskof epistaxis, thereby avoiding new wounds in the nasal cavity asassociated with the removal of non-fragmentable nasal dressings.

TABLE 2 Absorption behavior of foams of PEG containing PU's at 37° C. inbuffer solution. Mean Mean Mean Mean Increase in increase in increaseincrease weight (x weight (x of foam in foam Time in dry weight) dryweight) diameter (%) diameter (%) buffer Foam A Foam B Foam A Foam B10-40 min 21.8 23.7 −1.56 −0.40 3 hrs-14 days 22.3 22.7 2.11 0.68 FoamA: polyurethane based on gly/cap (50/50) pre-polymer with 25 wt % PEGFoam B: polyurethane based on gly/lac/cap (40/20/40) pre-polymer with 25wt % PEG

What is claimed is:
 1. Biodegradable absorbent foam, suitable forpacking antrums or other cavities of a human or animal body, comprisinga phase-separated polymer including an amorphous segment and acrystalline segment and wherein said amorphous segment comprises ahydrophilic segment, wherein said amorphous segment comprisespolyethyleneglycol, polypropyleneglycol or polybutylene glycol, andwherein said biodegradable absorbent foam has a complete fragmentationtime ranging from 1 to 10 days.
 2. Biodegradable absorbent foamaccording to claim 1, wherein said phase-separated polymer is of aformula (I):—[R-Q¹[—R¹—Z¹—[R″—Z²—R′—Z³]_(p)—R″—Z⁴]_(q)—R′-Q²]-_(n)  (I), wherein Ris selected from one or more aliphatic polyesters, polyetheresters,polyethers, polyanhydrides and/or polycarbonates, and at least one Rcomprises a hydrophilic segment, R′ and R″ are independently C₂-C₈alkylene, optionally substituted with C₁-C₁₀ alkyl or C₁-C₁₀ alkylgroups substituted with protected S, N, P or O moieties and/orcomprising S, N, P or O in said C₂-C₈ alkylene, Z¹-Z⁴ are independentlyamide, urea or urethane, Q¹ and Q² are independently urea, urethane,amide, carbonate, ester or anhydride, n is an integer from 5-500, p andq are independently 0 or 1, provided that when q is 0, R is a mixture ofat least one crystalline polyester, polyetherester or polyanhydridesegment and at least one amorphous aliphatic polyester, polyether,polyanhydride and/or polycarbonate segment, wherein said amorphoussegment comprises polyethylene glycol, polypropyleneglycol, orpolybutylene glycol.
 3. Biodegradable absorbent foam according to claim1, wherein said phase-separated polymer is of a formula (II):—[R-Q¹-R′″-Q²-]_(n)  (II), wherein R is selected from one or morealiphatic polyesters, polyetheresters, polyethers, polyanhydrides and/orpolycarbonates, and at least one R comprises a hydrophilic segment, Q¹and Q² are independently urea, urethane, amide, carbonate, ester oranhydride, n is an integer from 5-500, and R′″ is chosen from R, or fromR′ or R″ wherein R′ and R″ are independently C₂-C₈ alkylene, optionallysubstituted with C₁-C₁₀ alkyl or C₁-C₁₀ alkyl groups substituted withprotected S, N, P or O moieties and/or comprising S, N, P or O in saidC₂-C₈ alkylene, provided that when R″ is R′ or R″, R is a mixture of atleast one crystalline polyester, polyetherester or polyanhydride segmentand at least one amorphous aliphatic polyester, polyether, polyanhydrideand/or polycarbonate segment and when R′″ is R, at least one crystallinepolyester, polyetherester or polyanhydride segment and at least oneamorphous aliphatic polyester, polyether, polyanhydride and/orpolycarbonate segment is provided in said phase-separated polymer,wherein said amorphous segment comprises polyethylene glycol,polypropyleneglycol, or polybutylene glycol.
 4. Biodegradable absorbentfoam according to claim 2, wherein said phase-separated polymer isobtained by reacting one or more pre-polymers according to a formula(III):A-R-A′  (III), with one or more diisocyanates of a formula (IV):O═C═N—R′—N═O  (IV), and optionally one or more chain extenders of aformula (V):B—R″—B′  (V), wherein A, A′, B and B′ are independently selected fromhydroxyl, carboxyl or amine.
 5. Biodegradable absorbent foam accordingto claim 4, wherein said phase-separated polymer is obtained by reactingat least two different pre-polymers according to formula (III) with oneor more diisocyanates of the formula (IV):O═N—R′—N═C═O  (IV).
 6. Biodegradable absorbent foam according to claim5, wherein said phase-separated polymer is obtained by reacting at leasttwo different compounds according to formula (III):A-R-A′  (III), with one or more diisocyanates of a formula (IV):O═C═N—R′—N═O  (IV), with one or more compounds of a formula (V):B—R″—B′  (V) wherein R is selected from one or more aliphaticpolyesters, polyetheresters, polyethers, polyanhydrides and/orpolycarbonates, and at least one R comprises a hydrophilic segment, R″is independently C₂-C₈ alkylene, optionally substituted with C₁-C₁₀alkyl or C₁-C₁₀ alkyl groups substituted with protected S, N, P or Omoieties and/or comprising S, N, P or O in said C₂-C₅ alkylene, Q¹ andQ² are independently urea, urethane, amide, carbonate, ester oranhydride, and A, A′, B and B′ are independently selected from hydroxyl,carboxyl or amine, in the presence of an activator selected from a groupconsisting of N-hydroxysuccinimide, carbonyldiimidazole, aldehyde,maleimide, dicyclohexyl carbodiimide (DCC) and derivatives thereof. 7.Biodegradable absorbent foam according to claim 3, wherein R′ is (CH₂)₄,R″ is (CH₂)₄, or both R′ and R″ are (CH₂)₄.
 8. Biodegradable absorbentfoam according to claim 3, wherein at least one R is derived from acyclic monomer of lactide (L, D or LD), glycolide, C-caprolactone,ε-valerolactone, trimethylene carbonate, tetramethylene carbonate,1,5-dioxepane-2-one, para-dioxanone, or combinations thereof. 9.Biodegradable absorbent foam according to claim 3, wherein at least oneR is an amorphous polyester derived from lactide and ε-caprolactone,with said amorphous polyester having a number average molecular weightbetween 1000 and 4000 g/mol.
 10. Biodegradable absorbent foam accordingto claim 1, wherein said crystalline segment comprises polyurethane. 11.Biodegradable absorbent foam according to claim 1, wherein saidamorphous segment comprises polyethyleneglycol in a content of 1-80 wt.% based on a total weight of said amorphous segment.
 12. Biodegradableabsorbent foam according to claim 11, characterized in that saidbiodegradable absorbent foam has a swellability of less than 5%, and afluid absorption capacity of 1500-2500% based on a dry weight of saidbiodegradable absorbent foam.
 13. Biodegradable absorbent foam accordingto claim 11, characterized in that said biodegradable absorbent foam hasa fluid absorption capacity of 0.5-0.99 g/cm³ or a density of 0.01-0.2g/cm³.
 14. Biodegradable absorbent foam according to claim 1, whereinsaid amorphous segment comprises polyethyleneglycol in a content of 5-60wt. %.
 15. Biodegradable absorbent foam according to claim 11, whereinsaid polyethylene glycol has a number average molecular weight of 150 to4000 g/mol.
 16. Biodegradable absorbent foam according to claim 11,wherein said phase-separated polymer is obtained by reacting one or morediisocyanates of the formula (IV):O═C═N—R′—N═C═O  (IV), with one or more chain extenders of the formula(V):B—R″—B′  (V), to form an intermediate complex of the formula (VII):B—R″—Z^(i)—R′—Z—R″—B′  (VII); by reacting one or more diisocyanates ofthe formula (IV) with one or more pre-polymers of the formula (III):A-R-A′  (III), to form an intermediate diisocyanate complex of theformula (IX):O═C═N—R′—Z^(i)—R—Z—R′—N═C═O  (IX); and by reacting said intermediatecomplex of the formula (VII) and said intermediate diisocyanate complexof the formula (IX), wherein A, A′, B, and B′ are independently selectedfrom hydroxyl, carboxyl, and amine.
 17. Biodegradable absorbent foam,suitable for packing antrums or other cavities of a human or animalbody, comprising a phase-separated polymer including an amorphoussegment and a crystalline segment and wherein said amorphous segmentcomprises a hydrophilic segment, wherein said amorphous segmentcomprises polyethyleneglycol, polypropyleneglycol or polybutyleneglycol, and wherein said biodegradable absorbent foam has a porosityranging from 85 to 99%.
 18. Biodegradable absorbent foam of claim 17,wherein said biodegradable absorbent foam has a complete fragmentationtime ranging from 1 to 10 days.
 19. Biodegradable absorbent foam,suitable for packing antrums or other cavities of a human or animalbody, comprising a phase-separated polymer including an amorphoussegment and a crystalline segment and wherein said amorphous segmentcomprises a hydrophilic segment wherein said phase-separated polymer isof a formula (I):—[R-Q¹[—R¹—Z¹—[R″—Z²—R′—Z³]_(p)—R″—Z⁴]_(q)—R′-Q²]-_(n)  (I), wherein Ris selected from one or more aliphatic polyesters, polyetheresters,polyethers, polyanhydrides and/or polycarbonates, and at least one Rcomprises a hydrophilic segment, R′ and R″ are independently C₂-C₈alkylene, optionally substituted with C₁-C₁₀ alkyl or C₁-C₁₀ alkylgroups substituted with protected S, N, P or O moieties and/orcomprising S, N, P or O in said C₂-C₈ alkylene, Z¹-Z⁴ are independentlyamide, urea or urethane, Q¹ and Q² are independently urea, urethane,amide, carbonate, ester or anhydride, n is an integer from 5-500, p andq are independently 0 or 1, provided that when q is 0, R is a mixture ofat least one crystalline polyester, polyetherester or polyanhydridesegment and at least one amorphous aliphatic polyester, polyether,polyanhydride and/or polycarbonate segment, wherein said amorphoussegment comprises polyethyleneglycol in a content of 1-80 wt. % based ona total weight of said amorphous segment, wherein said polyethyleneglycol has a number average molecular weight of 150 to 4000 g/mol. 20.Biodegradable absorbent foam according to claim 19, wherein saidpolyethylene glycol has a number average molecular weight of between 600and 2000 g/mol.